Monotherapy for the polysensitized patient

1. Monotherapy for the polysensitized patient • Noel Rodriguez-Perez, MD • Professor of pediatrics • State University of Tamaulipas, Mexico

2. Monotherapy for the polysensitized patient • Objectives • To review the evidence for efficacy of immunotherapy with the more prevalent single allergen. • To highlight the importance of dosing and optimal concentration for efficacy.

3. Prevalence of sensitization by testing 9 allergens 45.4 % 51.9 % 28.8 % 36.4 % 39.6 % 41.2 % 33 % 41.4% 37.2 % 29.7 % 22.6 % 49.1 % 21.4 % Whole population: 35.6% /11 355 subjects were sensitized Bousquet PJ. Clin Exp Allergy. 2007 37: 780-7.

4. Prevalences of positive SPT to 10 allergens in the US National Health and Nutrition Examination Surveys III • NHANES III • 10,508 subjects tested to 10 allergens between 1988-1994 • 54.3% + SPT to 1 or more allergens • 15.5% + SPT to a single allergen • 38.8% + SPT to 2 or more allergens • Mean 3.5, median 3 • HDM (28%), Perennial rye (27%), Short ragweed (26%), Cockroach (26%), Bermuda grass (18%) Percentage (%) Number of sensitizations Arbes SJ. J Allergy ClinImmunol 2005; 116: 377-383

5. Sensitization patterns to allergens in Childhood • Retrospective analysis of all sIgE tests in children 0–18 yrs • 9044 children tested. The ImmunoCap. sIgE ≥0.35 kU/l. • 60.1% were not sensitized • 39.9% were sensitized to 1 or more allergens: • 31.1% + sIgE to a single allergen • 47.4% + sIgE to 2 to 4 allergens • 21.5% + sIgE to 5 or more allergens % within age group Age (years) de Jong AB. Pediatr Allergy Immunol 2011; 22: 166-71

6. Clinical characteristics of polysensitized patients • Characteristics of polysensitized patients wit AR. The POLISMAIL study (Italy) • 418 subjects, age 3.5–65 years • 52.6% had AR and 47.4 had AR and asthma. • 90% of patients were polysensitized (3.6 allergns) • Polysensitized patients had more severe symptoms Number of cases of AR or AR + Asthma Ciprandi G. Eur Ann Allergy ClinImmunol 2008; 40: 77-83. Number of sensitizations • Aeroallergen sensitization in asthmatics • SPT to 1338 subjects 12-65 YoA. with asthma • 95% were sensitized to 1 or more allergens • 14% + sIgE to a single allergen • 81% + sIgE to 3 or more allergens • Average of +SPT 5 allergens Mean number of positive skin tests Craig TJ. J Allergy Clin Immunol 2008; 121: 671-7 Age group

7. The average allergic patient is polysensitized

8. Canonica GW. WAO Journal 2009; 2: 233-281.

9. Is specific immunotherapy with single allergen effective in polysensitized patients?

10. Sublingual immunotherapy

11. Response to sublingual immunotherapy with grass pollen extract: Monotherapy versus combination in a multiallergenextract • Methods • Single-center, randomized, double-blind, placebo-controlled trial with SLIT. • After an observational grass season, SLIT was administered for 10 months to 54 patients randomized to 1 of 3 arms: • Placebo • Timothy extract (19 μg Phl p 5/day) as monotherapy • Same dose of Timothy extract plus 9 additional pollen extracts. • Outcomes included: Symptom and medication scores, titrated nasal challenges, titrated skin prick tests, sIgE, IgG4 and INF-g. Amar SM. J Allergy Clin Immunol 2009; 124: 150-156

12. Response to sublingual immunotherapy with grass pollen extract: Monotherapy versus combination in a multiallergenextract Titrated nasal challenge *  Log10 Dose (BAU/mL) t Skin Prick Tests ** *  Log10 Dose (BAU/mL) Monotherapy Timothy Multiallergen IT Placebo Amar SM. J Allergy Clin Immunol 2009; 124: 150-156

13. Response to sublingual immunotherapy with grass pollen extract: Monotherapy versus combination in a multiallergenextract Timothy specific IgG4 *  Log10 IgG4 (µcg/mL) Monotherapy Timothy Multiallergen IT Placebo Amar SM. J Allergy Clin Immunol 2009; 124: 150-156

14. Efficacy of sublingual immunotherapy with house dust mite extract in polyallergen sensitized patients with allergic rhinitis • Objective • To compare the efficacy of SLIT with standardized HDM extract in monosensitized and polysensitized patients with allergic rhinitis. • Methods • This study was a prospective case series conducted at a tertiary referral center. • Patients with allergic rhinitis sensitized only to HDM were compared with patients sensitized to HDM and other unrelated allergens after 1 year of SLIT with house dust mite extract. • Medication scores (AMS) and total nasal symptoms score (TNSS), including rhinorrhea, sneezing, nasal obstruction, and itchy nose, were evaluated before and 1 year after SLIT. Lee JE. Ann Allergy Asthma Immunol 2011; 107: 79–84.

15. Efficacy of sublingual immunotherapy with house dust mite extract in polyallergen sensitized patients with allergic rhinitis Allergic symptoms in the monosensitized group Allergic symptoms in the polysensitized group p < 0.001 p < 0.001 Symptoms scores Symptoms scores Lee JE. Ann Allergy Asthma Immunol 2011; 107: 79–84.

16. Efficacy of sublingual immunotherapy with house dust mite extract in polyallergen sensitized patients with allergic rhinitis Comparison of changes symptoms score and medication score between the 2 groups. Total nasal symptom score (TNSS) Antiallergic medication score (AMS) Lee JE. Ann Allergy Asthma Immunol 2011; 107: 79–84.

17. Sublingual immunotherapy in polysensitized patients: effect on quality of life • Methods • 167 polysensitized patients with allergic rhinitis were prospectively evaluated • QOL was measured in all cases with the Rhinoconjunctivitis Quality of Life Questionnaire at baseline and after 1 year of SLIT • The mean number of sensitizations per patient was 3.65 • SLIT using one extract was given to 123 patients (73.6%), with 2 extracts to 31 patients (18.6%), and with more than 2 extracts to 13 patients (7.8%) Ciprandi G. J Investig Allergol Clin Immunol 2010; 20: 274-9.

18. Sublingual immunotherapy in polysensitized patients: effect on quality of life Changes in health-related quality of life scores before and after sublingual immunotherapy * * * * * * * Mean Scores Ciprandi G. J Investig Allergol Clin Immunol 2010; 20: 274-9.

19. Radulovic S. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD002893.

20. Optimal dose, efficacy, and safety of once-daily SLIT with a 5 –grass pollen tablet for seasonal allergic rhinitis • Randomized, double-blind, placebo-controlled study • 628 adults with grass pollen ARC received 1 of 3 doses of a standardized 5–grass pollen extract, or placebo, administered sublingually using a once-daily tablet formulation • The treatment was initiated 4 months before the estimated pollen season and continued throughout the season • Outcomes: ARC Total Symptom Score,(6 most common symptoms), rescue medication use, quality of life, and safety Didier A. J Allergy Clin Immunol 2007; 120: 1338-45.

21. Long-term clinical efficacy in grass pollen–induced RC after treatment with SQ-standardized grass allergy immunotherapy tablet • A randomized, double-blind, placebo-controlled, phase III trial • 257 Adults with a history of moderate-to-severe grass pollen induced rhinoconjunctivitis inadequately controlled by symptomatic medications were included. • Efficacy end points were rhinoconjunctivitis symptom and medication scores, quality of life, and percentages of symptom and medication free days. Durham SR. J Allergy Clin Immunol 2010;125:131-38.

22. Injective immunotherapy

23. Grass pollen immunotherapy as an effectivetherapy for childhood seasonal allergic asthma Details of subjects • A randomized, double-blind, placebo-controlled study assessing the efficacy of grass pollen SIT over 2 pollen seasons was performed. • Children (3-16 years) with a history of seasonal allergic asthma sensitized to grass pollen (P pratense) and requiring at least 200 μg of inhaled beclomethasone equivalent per day were enrolled. • The primary outcome measure was a combined asthma symptom-medication score during the second pollen season. • Secondary outcome measures included end-point titration skin prick testing and conjunctival and bronchial provocation testing to allergen, sputum eosinophilia, exhaled nitric oxide, and adverse events. Mild symptoms had only a minimal effect on daily life, moderate symptoms were defined as having a significant effect on at least 50% of days, and severe symptoms have a major effect on life with daily symptoms. Subjects only had mild symptoms on exposure to tree pollen or house dust mite. Roberts G. J Allergy Clin Immunol 2006;117:263-8.

24. Grass pollen immunotherapy as an effectivetherapy for childhood seasonal allergic asthma Change in cutaneous allergen reactivity Grass pollen counts and symptom-medication scores for the second summer Change in conjunctival allergen reactivity Asthma symptom-medication scores Change in bronchial allergen reactivity Roberts G. J Allergy Clin Immunol 2006;117:263-8.

25. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis Peak season • Double-blind, randomized, placebo-controlled trial • 410 subjects with seasonal ARC were randomized: • 203 to 100,000 SQ-U (20mcg Phl p5) • 104 to 10,000 SQ-U (2mcg Phl p5) • 103 to placebo • 347(85%) completed treatment. Pollen Grains/m3 week Symptoms • 276 / 347 (78%) subjects were polysensitized • The polysensitized group showed a similar degree of improvement in symptoms, medication use, RQLQ, and VAS scores compared with the whole study group. • Both active doses were effective, but 100,000 SQ-U was more effective than 10,000 SQ-U Score Frew A. J Allergy Clin Immunol 2006; 117: 319-25.

26. Functional rather than immunoreactive levels of IgG(4) correlate closely with clinical response to grass pollen immunotherapy Combined symptom and medication scores during the pollen season • This is an 8-month dose-response randomized double-blind placebo-controlled study • 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100,000 SQ-U, 10,000 SQ-U or placebo injections. • Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. • Allergen-specific IgG(4) titres and IgG-associated inhibitory activity were evaluated. Shamji MH. Allergy 2011; DOI: 10.1111/j.1398-9995.2011.02745.x.

27. Functional rather than immunoreactive levels of IgG(4) correlate closely with clinical response to grass pollen immunotherapy Time course and dose dependency of SC grass pollen immunotherapy–induced changes in allergen-specific IgG4 antibodies and serum inhibitory activities. Phleum pratense-specific IgG4 antibody levels were measured by enzyme-linked immunosorbent assay. Serum inhibitory activity was measured by (B) IgE-FAB assay Subcutaneous allergen immunotherapy is associated with increases in Phleum pratense-specific IgE antibodies and blunting of seasonal increases in IgE antibodies. ADVIA Centaur automated analyser measurement of IgE levels that included a ‘no-wash’ step to measure IgE-blocking factor. Shamji MH. Allergy 2011; DOI: 10.1111/j.1398-9995.2011.02745.x.

28. Immunotherapy: The Meta-Analyses. What have we Learned? Calderon MA, Boyle RJ, Penagos M, Sheik A. Immunol Allergy Clin North Am. 2011;31(2):159-73, vii.

29. Th17 Th1 Th2 T cell function balanced by Treg cells after single or multi-allergen SIT Ozdemir C, Kukuksezer U, Akdis M, Acdis CA.Ann Allergy Asthma Immunol. 2011;107:381–392. Jutel M, Akdis CA. Immunological mechanisms of allergen-specific immunotherapy. Allergy 2011; 66: 725–732. Th9 iTreg

30. Monotherapy for the polysensitized patient • CONCLUSIONS • The majority of AR and asthma patients are polysensitized • SIT (SCIT and SLIT) with single allergen is effective in polysensitized patients • Further head-to-head comparisons of the efficacy of SIT in polysensitized vs. monosensitized patients are required in the context of RCTs. • “Decision must be based on the allergen which causes:”* • The longest duration of symptoms per year • The most severe symptoms • A major impact on quality of life • Which is more difficult to avoid * Allergy 2010; 65: 1525–1530.